BZW1 Facilitates Glycolysis and Promotes Tumor Growth in Pancreatic Ductal Adenocarcinoma Through Potentiating eIF2α Phosphorylation

被引：45

作者：

Li, Zengxun ^{[1
]}

Ge, Yi ^{[1
]}

Dong, Jie ^{[1
]}

Wang, Hongwei ^{[1
]}

Zhao, Tiansuo ^{[1
]}

Wang, Xiuchao ^{[1
]}

Liu, Jing ^{[1
]}

Gao, Song ^{[1
]}

Shi, Lei ^{[2
]}

Yang, Shengyu ^{[3
]}

Huang, Chongbiao ^{[1
]}

Hao, Jihui ^{[1
]}

机构：

[1] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Pancreat Canc, Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China

[2] Tianjin Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Tianjin, Peoples R China

[3] Penn State Univ, Dept Cellular & Mol Physiol, Coll Med, Hershey, PA USA

来源：

GASTROENTEROLOGY | 2022年 / 162卷 / 04期

基金：

中国国家自然科学基金; 国家重点研发计划; 美国国家卫生研究院;

关键词：

BZW1; Glycolysis; eIF2a; PERK; PDAC; TRANSLATIONAL CONTROL; LACTATE-DEHYDROGENASE; MEDIATED TRANSLATION; GLUCOSE-METABOLISM; CANCER; PROTEIN; INITIATION; STRESS; ACTIVATION; MYC;

D O I：

10.1053/j.gastro.2021.12.249

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by severe metabolic stress due to fibrosis and poor vascularization. BZW1 is an eIF5-mimic protein involved in tumorigenesis and progression. The aim of this study was to investigate the role of BZW1 in metabolic stress resistance in PDAC. METHODS: BZW1 expression was evaluated in human PDAC tissue microarray and PDAC cells. Glycolysis regulation of BZW1 and its correlation with glycolysis-related genes was analyzed. Tumor growth, cell proliferation, and apoptosis were evaluated in mice xenograft tumors and patient-derived organoids. RESULTS: The results of bioinformatic screening identified that BZW1 was 1 of the top 3 genes favorable for tumor progression in PDAC. The analysis of our cohort confirmed that BZW1 was overexpressed in human PDAC tissues compared with nontumor tissues, and its abnormal expression was correlated with large tumor size and poor prognosis. BZW1 promoted cell proliferation and inhibited apoptosis in both mouse xenograft models and PDAC-derived organoids via facilitating glycolysis in the oxygen-glucose- deprivation condition. Mechanically, BZW1 served as an adaptor for PKR-like endoplasmic reticulum (ER) kinase (PERK), facilitated the phosphorylation of eIF2 alpha, promoted internal ribosome entry site-dependent translation of HIF1 alpha and c-Myc, and thereby boosted the Warburg effect. In organoid-based xenografts with high BZW1 levels, both the PERK/eIF2 alpha phosphorylation inhibitor GSK2606414 and ISRIB significantly suppressed tumor growth and prolonged animal survival. CONCLUSIONS: BZW1 is a key molecule in the internal ribosome entry site-dependent translation of HIF1 alpha/c-Myc and plays crucial roles in the glycolysis of PDAC. BZW1 might serve as a therapeutic target for patients with pancreatic cancer.

引用

页码：1256 / +

页数：30

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